?DESCRIPTION (provided by applicant): We recently witnessed major advances in both our understanding of melanoma and in the development of antimelanoma therapeutics. The limited success of anti-BRAF therapy fuelled a surge in genomic and more recently non-genomic pathways that enabled the bypass of BRAF-blockade as well as metastatic phenotype. Altered metabolism and cellular ER stress response are positioned at the nexus of melanoma resistance and metastatic phenotypes, and are the focus on our application, which interlinks the master regulators-MITF, PGC1 with the UPR sensing machinery. Specifically, our competitive renewal focuses on two of the most critical obstacles in the clinical management of melanoma-its invasiveness (propensity to metastasize) and the acquisition of drug resistance. These phenotypic changes are a result of the propensity of melanoma to adapt to harsh microenvironmental conditions including the deprivation of nutrients, oxygen tension, and treatment with various drugs. Accordingly, we hypothesize that coordinated changes in metabolic regulation and the unfolded protein response affects MITF and underlies drug-resistant and invasive phenotype in melanoma. Our preliminary results suggest that melanoma reprogramming involves novel connection between the MITF, PGC1, and ATF4/Siah1. Our three projects and two scientific cores are expected to develop new paradigms enabling a better understanding of melanoma plasticity-the underpinning of its reprogramming-and offer innovative therapeutic approaches to treat invasive and drug resistant disease. We have assembled a team with internationally renowned expertise in the field of melanoma (Goding, Ronai, and Bosenberg), metabolism (Smith and Kelly), and the unfolded protein response (Kaufman). These investigators will collaborate with expert leaders of our Metabolomics (Osterman) and Multiplex Drug Screening (Stern) Cores. Together we will (I): Define the role of UPR components (Siah1 isoform 2, ATF4, CHOP) in melanoma metastasis and resistance to therapy (II) Determine the role of proliferator-activated receptor ? coactivators (PGC-1?/?) and downstream signaling in melanoma and acquisition of drug resistance and (III) understand the role and regulation of a feedback loop between MITF and ATF4, and the resulting downstream metabolic alterations, in acquisition of the invasive and drug-resistant phenotype of melanoma. All three projects will rely on the support by cores allowing metabolomics assessment (Core B), validation in relevant human melanoma tumors and genetic models as well as synthetic lethal screen (Core C) and coordinated administration (Core A). Ultimately, our work is expected to identify new therapeutic strategies for overcoming drug resistance and metastatic disease in melanoma.